Oral mucositis is an important and painful consequence of chemotherapy and hematopoietic cell transplantation (HCT). Given the major negative impact of mucositis on health, the focus should be on prevention rather than simply palliation. The most promising novel intervention with applicability to pediatrics is external low level light (LLLT) therapy. Objective: The objectives of this planning grant are to a) model the dosimetry of external LLLT and optimize the device parameters for the planned clinical trial, b) develop the Phase 2 multicenter clinical trial, including the study design, manual of procedures, and the laboratory based biological aim, and c) identify and recruit study sites and investigators. The primary aim of the proposed clinical trial is to determine whether external LLLT applied once daily from initiation of conditioning until day +20 or discharge, in children and adolescents undergoing myeloablative autologous or allogeneic HCT, can reduce the duration of severe (grade 3 or 4) mucositis according to the World Health Organization (WHO) mucositis scale, when compared to sham external LLLT therapy. Methods: External LLLT dosimetry will be evaluated using pediatric head and neck MRI studies to obtain serial measurements of different tissues that will then be used to develop a sophisticated computational model. We plan to conduct a double blinded, sham-controlled randomized trial in which patients 4 to 21 years of age will be randomized 1:1:1 to receive true external LLLT (dose level 1), true external LLLT (dose level 2) or sham LLLT starting from conditioning, daily until day +20 post stem cell infusion, or until resolution of mucositis, whichever occurs first. The secondary endpoints will be ChIMES, a pain 10 point categorical rating scale, total systemic opioid administration and days of parenteral nutrition (PN). Saliva will be collected to conduct genetic studies to determine individual mucositis risk as well as makers of response to therapy. This study will enroll 271 eligible transplant recipients (246 estimated to be evaluable for the primary analysis). Significance: Oral mucositis is one of the most distressing complications of therapy in patients undergoing HCT and for children in particular, there are no approved therapies to prevent or treat this complication other than palliation with analgesics. External low level light therapy (LLLT) is a potentially efficacious, feasible intervention ideally suited for this population. An effective intervention would improve quality of life and reduce morbidity for all children undergoing myeloablative HCT.